Aminoalkanes



Patented May 30, 1944 AMINOALKANES Horace A. Shonle and Ewald Rolirmann,Indianapolis, 11111., assignors to Eli Lilly and Company, Indianapolis,Ind., a corporation of Indiana No Drawing. Application April 9, 1942,Serial No. 438,304

6 Claims.

Ephedrine is obtained frombe inhaled and considerable relief obtained inmany cases of congestion of the nasal passageby this mode ofadministration. Amphetamine, however, has the decided disadvantage ofmarkedly stimulating the central nervous system and is relatively toxic.

The compositions of this invention possess the desirable properties ofboth ephedrine and antphetamine but do not manifest some of the undesirable characteristics of these two materials. The compositions ofthis invention are Z-amino- 4-methylhexane and the acid addition saltsof 2 amino 4 methylhexane. The 2 amino d-methylhexane may .beadministered for the treatment of congestion of the nasal passage byinhalation, for it is more volatile than amphetamine. The 2-amino-4n1ethylhexane' and its acid addition salts are substantially less toxicthan amphetamine and its acid addition salts. Unlike ephedrine, whichinhibits the action of smooth muscles, the compositions of thisinvention stimulate these muscles. The Z-amino-dmethylhexane and itsacid addition salts increase the nasal volume to a greater extent thanephedrine or amphetamine. In addition, amino--methylhexane and its saltshave a negligible effect on the nervous system and are relativelynontoxic.

Aqueous solutions or solutions in physiological saline of2-amino-4-methylhexanesulfate up to 4 percent are well tolerated by thehuman mucosa and produce no subjective discomfort of any kind in thepatient. There is a notable absence of local tingling and of subsequentsystematic reaction, such as tremor, excitement or insomnia which aresome of the more common subjective symptoms produced by ephedrine andits acid addition salts.

The Z-amino--methylhexane may be administered topically, while the acidaddition salts of 2-amino-4-methylhexane may be administered orally,parenterally, or topically. For topical administration of the2-amino-4-methylhexane, it may be dissolved in a suitable solvent, such.as cottonseed oil o liquid petrolatum, or it may be incorporated in ajelly or ointment. or it may be utilized directly by inhalation. Theacidaddition salts of the Z-amino-i-inethylhexane are preferably dissolvedin water or physiological saline solution or a sugar solution, such asglucose. For topical administration, a water solution, such as anisotonic water solution, can be conveniently used, while for parenteraladministration physiological saline, an aqueous solution, or an isotonicsolution of the desired acid addition salt may be employed. Jellies may.also be used for topical administration and may be prepared byincorporating an acid addition salt of 2-amino-4-methylhexane in water,glycerin, and some viscous medium or thickening agent, such; as gumtragacanth, sodium algenate or methyl cellulose.

'In addition, the 2-amino-4-methylhexane or the acid addition salt of2-amino-4-methylheuane may be combined with local anesthetic bases.Preferably, an acid addition salt of 2- amino-i-methylhexane is employedwith an acid addition salt of the local anesthetiebase or the localanesthetic base itself. Such combinations may be used in any suitableform, such as solutions, jellies, or ointments. An especially usefulcombination is that obtained by incorporating the acid addition salt of2-amino-4-methylhex f ane with the acid addition salt of a local anes jthetic base in an aqueous solution.

Examples of local anesthetic bases as such or as their acid additionsalts for thej'purposesol this invention are:Cocaine-methylbenzoylecgonirle Pmcaine-p-aminobenzoyldiethylaminoethanol1 A-[2-methyl piperidinol-propyl,benzoate I p-Aminobenzoyl-dimethylamino-rnethylbutanol Lp-Aminobenzoyl-A-di-n-butyla.minopropanol .1

aminopropanol p Aminobenzoyl 2 '2 dimethyl 4 3 diethylqMonoisobutylaminoethyl-p-aminobenzoatePiperidinopropanediol-di-phenylurethane 2 butyloxyquinolinecarboxylicacid -,;4 dieth ethylene-diamine a .\-diethylaminopropylcinnamate Thecompositions of this invention are iii pared by any one of the followingmethods-i? 1. One molecular equivalent of 4 met I anone-2 is reactedwith slightly more molecular equivalent of hydroxylami' I ably, thehydroxylamine is prepared 'in'the iires ence of the 4-methylhexanone-2by reacting the hydrochloride or sulfate or other salt of thehydroxylamine with a suitable base, such as sodium carbonate or sodiumhydroxide. Desirably, the reaction mixture is agitated for a few hour toinsure the conversion of the 4-methylhexanone-z to 4-methylhexanone-2oxime. The resulting 4-methylhexanone-2 oxime separates and is dried byany suitable means, such as with. a dehydrating agent, for example,sodium sulfate or magnesium sulfate. After drying, 4-methylhexanone-2oxime is reduced with hydrogen by means of a catalyst, such as Raneynickel, or by reaction of sodium and a primary alcohol, such as ethanol.The resulting 2-amino-4-rgethylhexane may be purified by distillation.

2. Another method of preparing the 2-amino- 4-methylhexane of thisinvention is to react one molecular equivalent of 4-methylhexanone-2with approximately four molecular equivalents of formamide or ammoniumformate. The mixture is heated to a temperature of 185-190 C. andmaintained at that temperature until the liberation of ammoniumcarbonate ceases. This condition may be readily ascertained byobse'rving a condenser attached to the reaction mixture. The reactionproduct is separated from the excess formamide by adding water to themixture, agitating, and separating the reaction product, which isinsoluble in water, from the water solution. The reaction product isthen refluxed with an excess of mineral acid, such as concentratedhydrochloric or dilute sulfuric acid. Desirably, the reaction product isrefluxed for a period of from one to two hours, during which time theacid addition salt of 2-amino-4- methylhexane is formed. It the base2-amino-4- methyhexane is desired, the acid addition salt is treatedwith a suitable base, such as sodium carbonate or sodium hydroxide. Ifpurification is desired, it may be distilled.

3. A third method of preparing compositions of this invention is tosubject a quantity of 4- methylhexanone-2 to the action of ammonia andhydrogen in the presence of a suitable catalyst, such as Raney nickel.Desirably, an excess of ammonia and hydrogen is used and the reactionmay be conveniently performed in a bomb by dissolving the ammonia in asolvent, such as ethanol.

If acid addition salts of the base, 2-amino-4- methylhexane, aredesired, the 2-amino-4-methylhexane is reacted with an equivalent of thedesired acid. The reaction is almost immediate and can be carried out ina suitable solvent, such as ethyl ether, ethanol, or water. In thismanner the acid addition salts of 2-amino-4-methylhexane may be formed,such as the acetic, hydro-- bromic, hydrochloric, sulfuric, maleic,propionic, or malonic acid salts of 2-amino-4-methylhexane.

In the preparation of the 2-amino-4-methylhexane or the acid additionsalts of 2-amino-4- methylhexane by the methods outlined herein, racemicmixtures of the d and 1 forms of 2- amino-4-methylhexane or the acidaddition salts of 2 amino 4 methylhexane result. These racemic mixturesmay be removed, if desired, by any of the well-known methods and, afterresolution, the d or the 1 form may be used alone as a vasoconstrictoror for other purposes instead of the racemic mixtures.

Typicalexamples of the compositions of this Is ylhexane.

In a 2-liter flask equipped with a stirrer and thermometer is placed g.(0.52 mol) of hydroxylamine hydrochloride and 175 cc. of cold water.This mixture is stirred until solution is complete. To this solution isadded g. (1 mol) of 4-methy1hexanone-2. The mixture is stirred and asolution of 50 g. (0.5 mol) of anhydrous sodium carbonate in about cc.of water is added through a dropping funnel. This addition is regulatedso that the temperature does not rise above 50 C. During this time 4-methylhexanone-2 oxime is formed. The stirring is continued for 1 to 2hours after the addition is completed. The mixture separates into twolayers, a water layer and a water-immiscible layer. The water-immisciblelayer, which contains the 4-methylhexanone-2 oxime, is washed with waterand dried with magnesium sulfate or sodium sulfate.

' A solution of 80 g. of crude dry 4-methylhexanone-2 oxime in 1800 cc.of absolute ethanol is heated to boiling in a 5-liter flask equippedwith an efficient reflux condenser. The source of heat is withdrawn andapproximately 200 g. of sodium metal is added as rapidly as possiblewithout essential loss of the ethanol. During this time the2-amino-4-methylhexane is formed. When all of the sodium is added andreacted, the mixture is cooled and diluted with about 1500 cc. of water.The mixtur'e is distilled through an emcient condenser until no more2-amino-4-methylhexane comes over. The distillate is adjusted to aboutpH 6 with hydrochloric acid and the solvents removed by heating invacuum. The resid-- ual material is cooled and made alkaline with strongsodium hydroxide solution. The Z-amino- 4-methylhexane is separated fromthe lower water layer and dried first over solid potassium hydroxide andthen over magnesium sulfate. The product, which is2-amino-4-methylhexane, may be distilled as a colorless liquid, B. P.about 131-133 C. uncorrected.

'Example 2.Preparation of 2-amino-4-methylhexane.

To a mixture of 20 g. of Raney nickel catalyst and 50 g. of4-methy1hexanone-2 contained in a steel bomb is added cc. of coldabsolute ethanol which has been saturated with anhydrous ammonia at 5 C.The resultingmixture is shaken for 3 hours with hydrogen at a pressureof 10 to 150 atmospheres at a temperature of 70 to 100? C. The catalystis removed by filtration and the filtrate subjected to fractionaldistillation through an efflcient fractionating column. The fractionboiling at about 131-133 C. consists of 2-amino-4-methy1hexane.

Example 3.Preparation of 2-amino-4-methylhexane.

A mixture of 250 g. (4 mols) of ammonium formate and 115 g. (1 mol) of4-methylhexanone-2 is heated in a 1-liter flask equipped with athermometer well and an 8-inch Vigreaux column. The top of the Vigreauxcolumn is connected to a condenser of large bore set for distillation.The mixture is heated from 150 to C. until distillation stops. Theketone which has distilled'over is separated and returned to thereaction flask and the heating continued. Water, carbon dioxide andammonia are formed as by-products in the reaction. The reaction re-2,850,318 quires approximately 8 to 10 hoursto complete.

During this time the formyl derivative of 2- aminoi-methylhexane isformed. When the reaction is completed the mixture is shaken with waterand the water-insoluble material separated, The water-insoluble materialis refluxed with 150 cc. of concentrated hydrochloric acid for about twohours. During this time the hydrochloride of 2-amino-4-methylhexane isformed. The aqueous solution of the hydrochloride after being freed fromany unchanged ketone, as by steam distillation, is cooled and madealkaline with strong sodium hydroxide solution. The separated2-amino-4-methylhexane is dried first with solid potassium hydroxide andthen. with anhydrous magnesium sulfate. The 2-amino-4- methylhexane isdistilled as a colorless liquid, boiling at about 13l-133 1C.uncorrected.

. In this preparation formamide may be used instead of ammonium formatewith good results. As in the case with ammonium formate best results areobtained by using an excess of formamide.

Eatample 4.Preparation of z-aminoi-meth ylhexane.

A mixture of 97 g. (0.75 mol) of 4-methylhexanone-2 oxime, 100 cc. ofethanol and 8.0 g. of Raney nickel catalyst is shaken with hydrogen at15 to 150 atmospheres pressure and a temperature of 75-100 C. for 5hours. During this time 2eamino-4-methylhexane is formed. The catalystis removed by filtration and the filtrate subjected to fractionaldistillation. The material boiling at about 131-133 C. uncorrected is001- lected separately and comprises the desired amine,2-amino-4-methylhexane.

Example 5.--Preparation of 2-amino-4-methylhexane sulfate.

A mixture of 75 g. of 2-amino-4-methylhexane, 200 cc. of absoluteethanol and 340 cc. of aqueous 2N sulfuric acid is evaporated to drynesson a steam bath. During thistimethe 2-amino-4- methylhexane sulfate isformed. The white solid is powdered and washed on a Buchner funnel firstwith ethyl ether-ethanol (1:1) and then with dry ethyl ether. The whitesolid is dried at 60-70 C. in an air oven. The product, which is2-amino-4-methylhexane sulfate, does not have a definite melting point.'It is very soluble in water and sparingly soluble in absolute ethanol.It contains a molecule of water of crystallization.

Other acid addition salts of 2-amino-4-methylhexane may be formed byreacting the 2-amino- 4-methylhexane with the required acid. Forexample,2-amino-4-methylhexane-n-hexyl sulfonate may be produced by reacting2-amino-4- methylhexane dissolved in a suitable solvent, such as ethylether, with a solution of n-hexyl sulfonic acid dissolved in ethylether. Likewise, 2- amino 4 methylhexane malate, 2 amino-4- methylhexanebenzoate, 2.-amino-4-methylhexane glycolate, Z-amino-i-methylhexanenicotinate, 2-amino-4-methylhexane maleate, z-aminoi-methylhexanegluconate, 2-amino-4-methylhexane phosphate, and 2-amino-4-methylhexanesuccinate may be prepared by reacting z-aminoi-methylhexane, dissolvedin a suitable'solvent, with malic acid, benzoic acid, glycolic acid,nicotinic acid, maleic acid, gluconic acid, phosphoric acid, or succinicacid respectively.

Example 6.Preparation of 2-amino-4-methylhexane inhalant compound.

lowing in approximately cc. of liquid petrolatum:

2-amino-4-methylhexane g 1 Menthol do-.. .75 Camphor do .75 Oil of thymecc .3 Liquid petrolatum to make do 100 Example 7.Preparation of2-amino-4-methylhexane sulfate jelly.

An effective 2-amino-4-methylhexane sulfate jelly is prepared bycompounding the following in; gredients:

, Grams z-aminoi-methylhexane sulfate c l Glycerin 15 Tragacanth 1Methyl salicylate .01 Sodium phosp .2 Water to make 10 Example8.Preparation of Z-amino-ri-methylhexane ointment.

An effective ointment ofv 2-amino-4-methylhexane is compounded from thefollowing in- Example 9.-Preparation of solution of acid addition saltsof z-aminoi-methylhexane.

An effective solution of z-amino-i-methylhexane sulfate for use as anasal spray is compounded from the following ingredients:

Chlorobutanol g- .5 2-amino-4-methylhexane sulfate do c 1 Physiologicalsaline solution cc 100 In Examples 7 and 8, acid addition salts of 2-amino-4-methylhexane such as those described in Example 5 may be usedinstead of 2-amino-4- methylhexane, while in Example 6 oil-soluble acidaddition saltssuch as 2-amino-4-methylhexane oleate may be employedinstead of the 2-amino-4-methylhexane. In addition, various othertherapeutic compositions may be substituted for the menthol, camphor,methyl salicylate and other ingredients used in the typical Examples 6,7, and 8. The proportion of all ingredients in these examples may bevaried within wide limits, it being understood that these examples aremerely typical of a wide variety of solutions, jellies, and ointmentswhich may be prepared with the compositions of this invention.

What is claimed is:

1. A composition selected from the class which consists of2-amino-4-methylhexane and acid addition salts of2-amino-4-methylhexane.

2. z-amino-i-methylhexane. I

3. An acid addition salt of 2-amino-4-methylhexane.

4. A solution of a composition selected from the class consisting of2-amino-4-methylhexane and acid addition salts of2-amino-4-methylhexane.

5. An isotonic solution of an acid addition salt of2-amino-4-methylhexane.

6. A 2- amino-4-methylhexane sulfate.

HDRACE A. SHONLE EWALD ROHRMANN.

